In today’s technology- and procedure-driven medical environment, the importance of carefully gathering information from patient inquiry and examination is at risk of losing its primacy. The history (and physical examination) remains the vital starting point for the evaluation of any clinical problem.1,2,3
GENERAL SYMPTOMS AND SIGNS
Performance status (PS) is used to establish semiquantitatively the extent of a patient’s disability. This status is important in evaluating patient comparability in clinical trials, in determining the likely tolerance to cytotoxic therapy, and in evaluating the effects of therapy. Table 1–2 presents a well-founded set of criteria for measuring PS.4 An abbreviated version sometimes is used, as proposed by the Eastern Cooperative Oncology Group (Table 1–3).5
Table 1–2.Criteria of Performance Status (Karnofsky Scale)4 ||Download (.pdf) Table 1–2. Criteria of Performance Status (Karnofsky Scale)4
|Able to carry on normal activity; no special care is needed. |
|100% ||Normal; no complaints, no evidence of disease |
|90% ||Able to carry on normal activity; minor signs or symptoms of disease |
|80% ||Normal activity with effort; some signs or symptoms of disease |
|Unable to work; able to live at home, care for most personal needs; a varying amount of assistance is needed. |
|70% ||Cares for self; unable to carry on normal activity or to do active work |
|60% ||Requires occasional assistance but is able to care for most personal needs |
|50% ||Requires considerable assistance and frequent medical care |
|Unable to care for self; requires equivalent of institutional or hospital care; disease may be progressing rapidly. |
|40% ||Disabled; requires special care and assistance |
|30% ||Severely disabled; hospitalization is indicated though death not imminent |
|20% ||Very sick; hospitalization necessary; active supportive treatment necessary |
|10% ||Moribund; fatal processes progressing rapidly |
|0% ||Dead |
Table 1–3.Eastern Cooperative Oncology Group Performance Status5 ||Download (.pdf) Table 1–3. Eastern Cooperative Oncology Group Performance Status5
|Grade ||Activity |
|0 ||Fully active, able to carry on all predisease performance without restriction |
|1 ||Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light housework, office work |
|2 ||Ambulatory and capable of all self-care but unable to carry out any work activities; up and about more than 50% of waking hours |
|3 ||Capable of only limited self-care, confined to bed or chair more than 50% of waking hours |
|4 ||Completely disabled; cannot carry on any self-care; totally confined to bed or chair |
|5 ||Dead |
Weight loss is a frequent accompaniment of many serious diseases, including primary hematologic malignancies, but it is not a prominent accompaniment of most hematologic diseases. Many “wasting” diseases, such as disseminated carcinoma and tuberculosis, cause anemia, and pronounced emaciation should suggest one of these diseases rather than anemia as the primary disorder.
Fever is a common early manifestation of the aggressive lymphomas or acute leukemias as a result of pyrogenic cytokines (e.g., interleukin [IL]-1, IL-6, and IL-8) released as a reflection of the disease itself. After chemotherapy-induced cytopenias or in the face of accompanying immunodeficiency, infection is usually the cause of fever. In patients with “fever of unknown origin,” lymphoma, particularly Hodgkin lymphoma, should be considered. Occasionally, primary myelofibrosis, acute leukemia, advanced myelodysplastic syndrome, and other lymphomas may also cause fever. In rare patients with severe pernicious anemia or hemolytic anemia, fever may be present. Chills may accompany severe hemolytic processes and the bacteremia that may complicate the immunocompromised or neutropenic patient. Night sweats suggest the presence of low-grade fever and may occur in patients with lymphoma or leukemia.
Fatigue, malaise, and lassitude are such common accompaniments of both physical and emotional disorders that their evaluation is complex and often difficult. In patients with serious disease, these symptoms may be readily explained by fever, muscle wasting, or other associated findings. Patients with moderate or severe anemia frequently complain of fatigue, malaise, or lassitude and these symptoms may accompany the hematologic malignancies. Fatigue or lassitude may occur also with iron deficiency even in the absence of sufficient anemia to account for the symptom. In slowly developing chronic anemias, the patient may not recognize reduced exercise tolerance, or other loss of physical capabilities except in retrospect, after a remission or a cure has been induced by appropriate therapy. Anemia may be responsible for more symptoms than has been traditionally recognized, as suggested by the remarkable improvement in quality of life of most uremic patients treated with erythropoietin.
Weakness may accompany anemia or the wasting of malignant processes, in which cases it is manifest as a general loss of strength or reduced capacity for exercise. The weakness may be localized as a result of neurologic complications of hematologic disease. In vitamin B12 deficiency (e.g., pernicious anemia), there may be weakness of the lower extremities, accompanied by numbness, tingling, and unsteadiness of gait. Peripheral neuropathy also occurs with monoclonal immunoglobulinemias. Weakness of one or more extremities in patients with leukemia, myeloma, or lymphoma may signify central or peripheral nervous system invasion or compression as a result of vertebral collapse, a paraneoplastic syndrome (e.g., encephalitis), or brain or meningeal involvement. Myopathy secondary to malignancy occurs with the hematologic malignancies and is usually manifest as weakness of proximal muscle groups. Foot drop or wrist drop may occur in lead poisoning, amyloidosis, systemic autoimmune diseases, or as a complication of vincristine therapy. Paralysis may occur in acute intermittent porphyria.
SPECIFIC SYMPTOMS OR SIGNS
Headache may be the result of a number of causes related to hematologic diseases. Anemia or polycythemia may cause mild to severe headache. Invasion or compression of the brain by leukemia or lymphoma, or opportunistic infection of the central nervous system by Cryptococcus or Mycobacterium species, may also cause headache in patients with hematologic malignancies. Hemorrhage into the brain or subarachnoid space in patients with thrombocytopenia or other bleeding disorders may cause sudden, severe headache.
Paresthesias may occur because of peripheral neuropathy in pernicious anemia or secondary to hematologic malignancy or amyloidosis. They may also result from therapy with vincristine.
Confusion may accompany malignant or infectious processes involving the brain, sometimes as a result of the accompanying fever. Confusion may also occur with severe anemia, hypercalcemia (e.g., myeloma), thrombotic thrombocytopenic purpura, or high-dose glucocorticoid therapy. Confusion or apparent senility may be a manifestation of pernicious anemia. Frank psychosis may develop in acute intermittent porphyria or with high-dose glucocorticoid therapy.
Impairment of consciousness may be a result of increased intracranial pressure secondary to hemorrhage or leukemia or lymphoma in the central nervous system. It may also accompany severe anemia, polycythemia, hyperviscosity secondary, usually, to an immunoglobulin (Ig) M monoclonal protein (uncommonly IgA or IgG) in the plasma, or a leukemic hyperleukocytosis syndrome, especially in chronic myelogenous leukemia.
Conjunctival plethora is a feature of polycythemia and pallor a result of anemia. Occasionally blindness may result from retinal hemorrhages secondary to severe anemia and thrombocytopenia or blurred vision resulting from severe hyperviscosity resulting from macroglobulinemia or extreme hyperleukocytosis of leukemia. Partial or complete visual loss can stem from retinal vein or artery thrombosis. Diplopia or disturbances of ocular movement may occur with orbital tumors or paralysis of the third, fourth, or sixth cranial nerves because of compression by tumor, especially extranodal lymphoma, extramedullary myeloma, or myeloid (granulocytic) sarcoma.
Vertigo, tinnitus, and “roaring” in the ears may occur with marked anemia, polycythemia, hyperleukocytic leukemia, or macroglobulinemia-induced hyperviscosity. Ménière disease was first described in a patient with acute leukemia and inner ear hemorrhage.
Nasopharynx, Oropharynx, and Oral Cavity
Epistaxis may occur in patients with thrombocytopenia, acquired or inherited platelet function disorders, and von Willebrand disease. Anosmia or olfactory hallucinations occur in pernicious anemia. The nasopharynx may be invaded by a granulocytic sarcoma or extranodal lymphoma; the symptoms are dependent on the structures invaded. The paranasal sinuses may be involved by opportunistic organisms, such as fungus in patients with severe, prolonged neutropenia. Pain or tingling in the tongue occurs in pernicious anemia and may accompany severe iron deficiency or vitamin deficiencies. Macroglossia occurs in amyloidosis. Bleeding gums may occur with bleeding disorders. Infiltration of the gingiva with leukemic cells occurs notably in acute monocytic leukemia. Ulceration of the tongue or oral mucosa may be severe in the acute leukemias or in patients with severe neutropenia. Dryness of the mouth may be caused by hypercalcemia, secondary, for example, to myeloma. Dysphagia may be seen in patients with severe mucous membrane atrophy associated with chronic iron-deficiency anemia.
Painless swelling in the neck is characteristic of lymphoma but may be caused by a number of other diseases as well. Occasionally, the enlarged lymph nodes of lymphomas may be tender or painful because of secondary infection or rapid growth. Painful or tender lymphadenopathy is usually associated with inflammatory reactions, such as infectious mononucleosis or suppurative adenitis. Diffuse swelling of the neck and face may occur with obstruction of the superior vena cava due to lymphomatous compression.
Both dyspnea and palpitations, usually on effort but occasionally at rest, may occur because of anemia or pulmonary embolism. Congestive heart failure may supervene, and angina pectoris may become manifest in anemic patients. The impact of anemia on the circulatory system depends in part on the rapidity with which it develops, and chronic anemia may become severe without producing major symptoms; with severe acute blood loss, the patient may develop shock with a nearly normal hemoglobin level, prior to compensatory hemodilution. Cough may result from enlarged mediastinal nodes compressing the trachea or bronchi. Chest pain may arise from involvement of the ribs or sternum with lymphoma or multiple myeloma, nerve-root invasion or compression, or herpes zoster; the pain of herpes zoster usually precedes the skin lesions by several days. Chest pain with inspiration suggests a pulmonary infarct, as does hemoptysis. Tenderness of the sternum may be quite pronounced in chronic myelogenous or acute leukemia, and occasionally in primary myelofibrosis, or if intramedullary lymphoma or myeloma proliferation is rapidly progressive.
Dysphagia has already been mentioned under “Nasopharynx, Oropharynx, and Oral Cavity” above. Anorexia frequently occurs but usually has no specific diagnostic significance. Hypercalcemia and azotemia cause anorexia, nausea, and vomiting. A variety of ill-defined gastrointestinal complaints grouped under the heading “indigestion” may occur with hematologic diseases. Abdominal fullness, premature satiety, belching, or discomfort may occur because of a greatly enlarged spleen, but such splenomegaly may also be entirely asymptomatic. Abdominal pain may arise from intestinal obstruction by lymphoma, retroperitoneal bleeding, lead poisoning, ileus secondary to therapy with the vinca alkaloids, acute hemolysis, allergic purpura, the abdominal crises of sickle cell disease, or acute intermittent porphyria. Diarrhea may occur in pernicious anemia. It also may be prominent in the various forms of intestinal malabsorption, although significant malabsorption may occur without diarrhea. In small-bowel malabsorption, steatorrhea may be a notable feature. Malabsorption may be a manifestation of small-bowel lymphoma. Gastrointestinal bleeding related to thrombocytopenia or other bleeding disorder may be occult but often is manifest as hematemesis or melena. Hematochezia can occur if a bleeding disorder is associated with a colonic lesion. Constipation may occur in the patient with hypercalcemia or in one receiving treatment with the vinca alkaloids.
Genitourinary and Reproductive Systems
Impotence or bladder dysfunction may occur with spinal cord or peripheral nerve damage caused by one of the hematologic malignancies or with pernicious anemia. Priapism may occur in hyperleukocytic leukemia, essential thrombocythemia, or sickle cell disease. Hematuria may be a manifestation of hemophilia A or B. Red urine may also occur with intravascular hemolysis (hemoglobinuria), myoglobinuria, or porphyrinuria. Injection of anthracycline drugs or ingestion of drugs such as phenazopyridine (Pyridium) regularly causes the urine to turn red. The use of deferoxamine mesylate (Desferal) may result in rust colored urine. Amenorrhea may also be induced by certain drugs, such as antimetabolites or alkylating agents. Menorrhagia is a common cause of iron deficiency, and care must be taken to obtain a history of the number of prior pregnancies and an accurate assessment of the extent of menstrual blood loss. Semiquantification can be obtained from estimates of the number of days of heavy bleeding (usually <3), the number of days of any bleeding (usually <7), number of tampons or pads used (requirement for double pads suggests excessive bleeding), degree of blood soaking, and clots formed, and inquiries such as, “Have you experienced a gush of blood when a tampon is removed?” However, an objective distinction between menorrhagia (loss of more than 80 mL blood per period) and normal blood loss can best be made by a visual assessment technique using pictorial charts of towels or tampons.6 Menorrhagia may occur in patients with bleeding disorders.
Back pain may accompany acute hemolytic reactions or be a result of involvement of bone or the nervous system in acute leukemia or aggressive lymphoma. It is one of the most common manifestations of myeloma.
Arthritis or arthralgia may occur with gout secondary to increased uric acid production in patients with hematologic malignancies, especially acute lymphocytic leukemia in childhood, myelofibrosis, myelodysplastic syndrome, and hemolytic anemia. They also occur in the plasma cell dyscrasias, acute leukemias, and sickle cell disease without evidence of gout, and in allergic purpura. Arthritis may accompany hemochromatosis, although the association has not been carefully established. In the latter case the arthritis starts typically in the small joints of the hand (second and third metacarpal joints), and episodes of acute synovitis may be related to deposition of calcium pyrophosphate dehydrate crystals. Hemarthroses in patients with severe bleeding disorders cause marked joint pain. Autoimmune diseases may present as anemia and/or thrombocytopenia, and arthritis appears as a later manifestation. Shoulder pain on the left may be a result of infarction of the spleen and on the right of gall bladder disease associated with chronic hemolytic anemia such as hereditary spherocytosis. Bone pain may occur with bone involvement by the hematologic malignancies; it is common in the congenital hemolytic anemias, such as sickle cell anemia, and may occur in myelofibrosis. In patients with Hodgkin lymphoma, ingestion of alcohol may induce pain at the site of any lesion, including those in bone. Edema of the lower extremities, sometimes unilateral, may occur because of obstruction to veins or lymphatics by lymphomatous masses or from deep venous thrombosis. The latter can also cause edema of the upper extremities.
Skin manifestations of hematologic disease may be of great importance; they include changes in texture or color, itching, and the presence of specific or nonspecific lesions. The skin in iron-deficient patients may become dry, the hair dry and fine, and the nails brittle. In hypothyroidism, which may cause anemia, the skin is dry, coarse, and scaly. Jaundice may be apparent with pernicious anemia or congenital or acquired hemolytic anemia. The skin of patients with pernicious anemia is said to be “lemon yellow” because of the simultaneous appearance of jaundice and pallor. Jaundice may also occur in patients with hematologic malignancies, especially lymphomas, as a result of liver involvement or biliary tract obstruction. Pallor is a common accompaniment of anemia, although some severely anemic patients may not appear pale. Erythromelalgia may be a troublesome complication of polycythemia vera. Patchy plaques or widespread erythroderma occur in cutaneous T-cell lymphoma (especially Sézary syndrome) and in some cases of chronic lymphocytic leukemia or lymphocytic lymphoma. The skin is often involved, sometimes severely, in graft-versus-host disease following hematopoietic cell transplantation. Patients with hemochromatosis may have bronze or grayish pigmentation of the skin. Cyanosis occurs with methemoglobinemia, either hereditary or acquired; sulfhemoglobinemia; abnormal hemoglobins with low oxygen affinity; and primary and secondary polycythemia. Cyanosis of the ears or the fingertips may occur after exposure to cold in individuals with cryoglobulins or cold agglutinins.
Itching may occur in the absence of any visible skin lesions in Hodgkin lymphoma and may be extreme. Mycosis fungoides or other lymphomas with skin involvement may also present as itching. A significant number of patients with polycythemia vera will complain of itching after bathing.
Petechiae and ecchymoses are most often seen in the extremities in patients with thrombocytopenia, nonthrombocytopenic purpura, or acquired or inherited platelet function abnormalities and von Willebrand disease. Unless secondary to trauma, these lesions usually are painless; the lesions of psychogenic purpura and erythema nodosum are painful. Easy bruising is a common complaint, especially among women, and when no other hemorrhagic symptoms are present, usually no abnormalities are found after detailed study. This symptom may, however, indicate a mild hereditary bleeding disorder, such as von Willebrand disease or one of the platelet disorders. Infiltrative lesions may occur in the leukemias (leukemia cutis) and lymphomas (lymphoma cutis) and are sometimes the presenting complaint. Monocytic leukemia has a higher frequency of skin infiltration than other forms of leukemia. Necrotic lesions may occur with intravascular coagulation, purpura fulminans, and warfarin-induced skin necrosis, or rarely with exposure to cold in patients with circulating cryoproteins or cold agglutinins.
Leg ulcers are a common complaint in sickle cell anemia and occur rarely in other hereditary anemias.
Drug therapy, either self-prescribed or ordered by a physician, is extremely common in our society. Drugs often induce or aggravate hematologic disease, and it is therefore essential that a careful history of drug ingestion, including beneficial and adverse reactions, should be obtained from all patients. Drugs taken regularly, including nonprescription medications, often become a part of the patient’s way of life and are forgotten or are not recognized as “drugs.”
Agents such as aspirin, laxatives, tranquilizers, medicinal iron, vitamins, other nutritional supplements, and sedatives belong to this category. Furthermore, drugs may be ingested in unrecognized form, such as antibiotics in food or quinine in tonic water. Specific, persistent questioning, often on several occasions, may be necessary before a complete history of drug use is obtained. It is very important to obtain detailed information on alcohol consumption from every patient. The four “CAGE” questions—about needing to cut down, being annoyed by criticism, having guilt feelings, and requiring a drink as a morning eye-opener—provide an effective approach to the history of alcohol use. Patients should also be asked about the use of recreational drugs. The use of “alternative medicines” and herbal medicines is common, and many patients will not consider these medications or may actively withhold information about their use. Nonjudgmental questioning may be successful in identifying agents in this category that the patient is taking. Some patients equate the term “drugs,” as opposed to “medicines,” with illicit drugs. Establishing that the examiner is interested in all forms of ingestants—prescribed drugs, self-remedies, alternative remedies, etcetera—is important to ensure getting the information required.
In addition to drugs, most people are exposed regularly to a variety of chemicals in the environment, some of which may be potentially harmful agents and result in a deleterious hematologic effect, such as anemia or leukopenia. An occupational history should explore exposure to potentially harmful chemicals. This information should be supplemented by inquiries about hobbies and other interests that result in work with chemicals, such as glues and solvents. When a toxin is suspected, the patient’s daily activities and environment should be carefully reviewed, as significant exposure to toxic chemicals may occur incidentally.
Vaccinations can be complicated by acute immune thrombocytopenia. In infants, this is most notable after measles, mumps, rubella (MMR) vaccine. This occurrence is approximately 1 in 25,000 children vaccinated, occurs within 6 weeks of vaccination, and in the majority of occurrences is self-limited. There is no evidence that children with antecedent immune thrombocytopenia are at risk of recurrence after MMR vaccination.7 Analysis, thus far, shows rare cases in following administration of other vaccines (hepatitis A, diphtheria-pertussis-tetanus, or varicella) administered to older children and adolescents and significant risk has not been ascertained.8
Children who are breastfed without iron supplementation may develop iron-deficiency anemia. Nutritional information can be useful in deducing the possible role of dietary deficiency in anemia. The avoidance of certain food groups, as might be the case with vegetarians, or the ingestion of uncooked fish can be clues to the pathogenesis of megaloblastic anemia.
A carefully obtained family history may be of great importance in the study of patients with hematologic disease (Chap. 10). In the case of hemolytic disorders, questions should be asked regarding jaundice, anemia, and gallstones in relatives. In patients with disorders of hemostasis or venous thrombosis, particular attention must be given to bleeding manifestations or venous thromboembolism in family members. In the case of autosomal recessive disorders such as pyruvate kinase deficiency, the parents are usually not affected, but a similar clinical syndrome may have occurred in siblings. It is particularly important to inquire about siblings who may have died in infancy, as these may be forgotten, especially by older patients. When sex-linked inheritance is suspected, it is necessary to inquire about symptoms in the maternal grandfather, maternal uncles, male siblings, and nephews. In patients with disorders with dominant inheritance, such as hereditary spherocytosis, one may expect to find that one parent and possibly siblings and children of the patient have stigmata of the disease. Ethnic background may be important in the consideration of certain diseases such as α- and β-thalassemia, sickle cell anemia, glucose-6-phosphate dehydrogenase deficiency, hemoglobin E, and other inherited disorders that are prevalent in specific geographic areas, such as the Mediterranean basin or Southeast Asia.
Because of the frequency of infections with the human immunodeficiency viruses, it is important to ascertain the sexual behavior of the patient, especially risk factors for transmission of HIV.
Ideally, the physician’s goal is to prevent illness, and opportunities exist for hematologists to prevent the development of hematologic disorders. These opportunities include identification of individual genetic risk factors and avoidance of situations that may make a latent disorder manifest. Prophylactic therapy, as for example in avoiding venous stasis in patients heterozygous for protein C deficiency or administering prophylactic heparin at the time of major surgery, is a more immediate aspect of prevention because it depends on the physician’s intervention. Hematologists may also prevent disease by reinforcing community medicine efforts. Examples include fostering the elimination of sources of environmental lead that may result in childhood anemia. Prenatal diagnosis can provide information to families as to whether a fetus is affected with a hematologic disorder.